Abstract B239: Inhibition of myeloproliferative neoplasms by combinations of JAK2 and PI3K inhibitors.

This study focuses on three main myeloproliferative neoplasms, namely, polycythaemia vera, essential thrombocytosis, and primary myelofibrosis. The main pathological causes of these three diseases are a mutation in the JAK2 protein or a mutation in the thrombopoietin receptor that arises in the hematopoietic stem/progenitor cells. Both type of mutations lead to constitutive activation of the JAK2 signaling pathways. Current JAK2 inhibitors in clinical trials are not expected to be selective and specific enough to suppress the multiple signaling pathways activated by the aberrant JAK2 signaling. Hence, we are seeking a combination treatment using a specific JAK2 inhibitor with another specific kinase inhibitor to inhibit the multiple signaling pathways activated by the constitutively active JAK2. Mouse Ba/F3 cells were engineered to express either JAK2 WT, or JAK2 V617F, or TpoR W515L, or TpoR JAK2 WT, or TpoR JAK2 V617F, or Bcr-abl. The effect of JAK2 inhibitors in combination with a panel of kinase inhibitors in an 8×8 constant ratio drug combination design were used to test for the inhibition of cell viability in the cell models. Calculation of drug synergism was carried out using the Chou-Talalay method. We found that JAK2 inhibitors synergized with PI3K inhibitors. The JAK2-PI3K inhibitors combination was specific for JAK2 signaling as survival of Ba/F3 cells expressing Bcr-abl was unaffected by this combination treatment. Balb/c mice inoculated with Ba/F3 cells expressing TpoR JAK2 V617F were found to have increased spleen weight. Our combination treatment could drastically reduce spleen weight compared to treatment with individual compound alone. The combination treatment also resulted in significant survival benefit in Balb/c mice inoculated with Ba/F3 cells expressing TpoR JAK2 V617F compared to untreated mice or mice given either compound alone. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B239.